Acute psychotic episodes have been associated with alcohol, hallucinogen, cannabis, or cocaine/stimulant use. Currently, there are no guidelines for the pharmacological treatment of individuals with psychosis associated with substance use beyond the acute episode, and specifically, no studies assessing the long-term efficacy of second generation antipsychotics in this population. Among the second generation antipsychotics, aripiprazole may be the optimal choice for long-term treatment of these subjects for the following reasons: 1) Its antipsychotic efficacy is similar to other second generation antipsychotics. 2) It is a prime candidate for the treatment of dopaminergic dysfunction found in addictive behaviors. It is the only approved D2 partial agonist available in the U.S. and has a modulating effect on dopaminergic function, i.e., acts as a D2 antagonist in dopamine-rich environment and D2 agonist in dopamine-poor environment (Travis et al. 2005). Converging evidence from animal and human studies suggests that dysfunction of the dopaminergic brain reward circuit is involved in the various aspects of drug addiction, including reinforcing responses to drugs during intoxication, activation during craving, and deactivation during withdrawal (Kalivas 2002). It has been suggested that decreases in dopamine receptors and dopamine release may induce a decreased sensitivity of reward circuits to stimulation by natural rewards (Noble et al. 1991; Volkow et al. 2002). In mice, aripiprazole antagonizes ethanol-, amphetamine-, and cocaine-induced locomotor stimulation, which suggest that aripiprazole decreases drug-induced hyperdopaminergia (Jerihag 2008; Leite et al. 2008). In human subjects, aripiprazole attenuates the discriminative-stimulus, cardiovascular effects, and subjectrated effects of d-amphetamine (Lile et al. 2005; Stoops et al. 2006). 3) Several studies suggest that it decreases substance use in subjects without and with psychosis. Martinotti et al (2007) reported on thirteen detoxified alcohol-dependent subjects who were treated with flexible doses of aripiprazole for 16 weeks. All subjects experienced reduced craving and a decrease ofthe SCL-90 General Severity Index with 6 patients maintaining sobriety during the study. Anton et al (2008) conducted a 12-week double-blind placebo-controlled study in 295 subjects with alcohol dependence. Compared to subjects on placebo, subjects treated with aripiprazole reported more positive subjective treatment effects and less overall severity of alcohol dependence at the end of the study. Kranzler et al (2008) found that aripiprazole decreases the euphoric effect of alcohol in 18 healthy subjects. Deseilles et al (2008) reported a decrease in cannabis use in one non-psychotic subject treated with aripiprazole. Beresford et al (2005) conducted a 8-week, open-label trial in 10 poorly compliant subjects with schizophrenia and co-occuring cocaine dependence and alcohol abuse. Six subjects completed the trial and had decreased positive urine tests for cocaine, and decreased craving for cocaine and alcohol. In Brown et al (2005), 20 antipsychotic-treated subjects were switched to 12- week open-label aripiprazole. Alcohol dependent subjects (n=17) had a decrease in dollars spent on alcohol and in craving. Subjects with cocaine-related disorders (n=9) had decreased cocaine craving. 5) Aripiprazole has antidepressant properties and is approved by the FDA as augmentation therapy in major depression (Berman et al. 2007). Subjects with psychotic disorders and co-occurring substance use disorders are prone to anhedonia, emotional flattening and low mood, increasing the risk of relapse to substance abuse, low adherence rates and poorer clinical outcomes. Hence, we hypothesize that aripiprazole will improve mood in subjects with psychotic episodes associated with substance use. 5) It has a relatively favorable side effect profile, including less risk of metabolic syndrome, prolactin elevation, and QTc interval prolongation compared to other atypicals (Chen et al. 2007; El-Sayeh et al. 2006). PRELIMINARY DATA From 2001 to 2007, we conducted a study comparing the effectiveness of randomly assigned open-label flexible dose treatment with olanzapine (2.5 to 20 mg per day) or risperidone (1 to 6 mg) in subjects aged 16 to 40 with a first episode of schizophrenia (75%), schizoaffective disorder (17%), or schizophreniform disorder (8%). The final study sample consisted of 112 subjects (70% male; mean age 23.3 (SD = 5.1) years). Lifetime prevalence rates of abuse or dependence were the highest for cannabis (44%), followed by alcohol (22%), and cocaine (4%). Nineteen subjects with cannabis use disorders (abuse or dependence; CUD) (39%) had alcohol use disorders (abuse or dependence) and seven CUD subjects (14%) had other substance use disorders (cocaine, n=5; hallucinogens, n=2; opiates, n=1; inhalants, n=1). 49.1% (95% Cl: 38.7%, 59.6%) of patients met response criteria. However, thirty percent (95% Cl: 13.5%, 46.2%) of subjects who met response criteria failed to maintain response. Marijuana use and alcohol use during treatment were significantly correlated and associated with failure to maintain response. Using a composite measure for our multivariate model, which included sex and medication assignment, both the composite substance use measure (hazard ratio=1.48; 95% Cl=1.04, 2.10; p<0.04) and poor premorbid social functioning (hazard ratio=1.14; 95% Cl=1.02, 1.28; p<0.03) were significant predictors of response instability. We also assessed if olanzapine (n=28) was more effective than risperidone (n=21) in first-episode patients with cannabis use disorders. Response rates of positive symptoms were 45% (95% Cl: 25%, 65%) with olanzapine and 54% (95% Cl: 29%, 79%) with risperidone. Survival curves did not differ between groups (log-rank test; p < 0.95) and there were no differences between treatment groups for cannabis use (56% in the olanzapine group vs. 35% in the risperidone group, p < 0.16) or alcohol use (52% in the olanzapine group vs. 40% in the risperidone group, p < 0.42). Thus, our results suggest that (1) olanzapine and risperidone have similar efficacy on psychotic symptoms and cannabis or alcohol use in subjects with cannabis use disorders and a first episode of psychosis; and (2) cannabis and alcohol use during treatment increases the risk of not sustaining response. These preliminary studies also demonstrate our ability to use second generation antipsychotics for treating psychotic patients with co-occurring substance use disorders during and after the acute episode.